US10441577B2 - Medicament for treatment of liver cancer - Google Patents

Medicament for treatment of liver cancer Download PDF

Info

Publication number
US10441577B2
US10441577B2 US14/131,059 US201214131059A US10441577B2 US 10441577 B2 US10441577 B2 US 10441577B2 US 201214131059 A US201214131059 A US 201214131059A US 10441577 B2 US10441577 B2 US 10441577B2
Authority
US
United States
Prior art keywords
alkyl
substituted
mapk14
unsubstituted
sorafenib
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US14/131,059
Other languages
English (en)
Other versions
US20150079154A1 (en
Inventor
Lars Zender
Ramona Rudalska
Daniel Dauch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Original Assignee
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP11173379A external-priority patent/EP2543372A1/de
Application filed by Helmholtz Zentrum fuer Infektionsforschung HZI GmbH filed Critical Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Priority to US14/131,059 priority Critical patent/US10441577B2/en
Assigned to HELMHOLTZ ZENTRUM FUER INFEKTIONSFORSCHUNG reassignment HELMHOLTZ ZENTRUM FUER INFEKTIONSFORSCHUNG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: Dauch, Daniel, RUDALSKA, Ramona, ZENDER, LARS
Publication of US20150079154A1 publication Critical patent/US20150079154A1/en
Application granted granted Critical
Publication of US10441577B2 publication Critical patent/US10441577B2/en
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a medicament and to a pharmaceutical composition, respectively, which is suitable for the treatment or prevention of liver cancer, especially hepatocellular carcinoma (HCC) in human patients.
  • liver cancer especially hepatocellular carcinoma (HCC) in human patients.
  • HCC hepatocellular carcinoma
  • the invention relates to a method for the treatment of liver cancer by administration of the pharmaceutical composition to a patient, and to a process for producing a medicament or pharmaceutical composition, respectively, which is suitable for the treatment of liver cancer.
  • liver cancer Today, the only curative options for the treatment of liver cancer are surgical resection or liver transplantation. However, at the time of diagnosis the majority of patients present with advanced tumor growth and are therefore not eligible for these treatment options. Liver cancer is a primarily chemoresistant tumor and only recently Llovet and coworkers described the multikinase inhibitor Sorafenib as the first systemic treatment which can prolong survival of patients with HCC. However, the treatment is costly and only yields a survival advantage of less than three month. Therefore, there is an urgent clinical need for the development of medicaments which increase efficiency over Sorafenib.
  • WO 2010/128259 A1 describes a pharmaceutical combination of Sorfenib with a vascular disrupting agent.
  • WO2005/009961 A2 describes a fluoro derivative of Sorafenib.
  • Sorafenib is described to inhibit proliferation of HCC cells and to induce apoptosis by inhibiting the phosphorylation of MEK, ERK and down-regulating cyclin D1 levels.
  • the invention achieves these objects by the features as defined by the claims, especially by providing a pharmaceutical composition, the composition comprising Sorafenib and, in addition to Sorafenib, an inhibitor of Mapk14 (p38 ⁇ kinase inhibitor) as a medicament for use in the treatment and/or in the prevention of cancer, especially liver cancer.
  • the inhibitor of Mapk14 activity is a pharmaceutical active agent which in combination with Sorafenib is used as a medicament for the treatment and/or prevention of liver cancer.
  • Sorafenib and the inhibitor of Mapk14 can be provided for joint administration, e.g.
  • the invention provides a combination of Sorafenib with an inhibitor of Mapk14 as a medicament for the treatment and/or prevention of liver cancer for joint or separate administration, as well as for a composition comprising a combination of Sorafenib and of an inhibitor of Mapk14, e.g.
  • the invention relates to the treatment of cancer, especially of liver cancer, by administration of this pharmaceutical composition, e.g by separate or simultaneous administration of Sorafenib and of the inhibitor of Mapk14 to a human suffering from cancer, especially from liver cancer.
  • the liver cancer is non-viral liver cancer or virally caused liver cancer.
  • an agent which inhibits the activity of Mapk14 increases the efficacy of Sorafenib, as a medicament in the treatment or prevention of liver cancer.
  • the inhibition of the activity of Mapk14 can be obtained by the inhibition of the expression of Mapk14 gene product or protein, inhibitors of the translation of the mRNA encoding Mapk14, and inhibitors of Mapk14 protein activity, e.g. kinase inhibitors, are comprised in the group of inhibitors of the activity of Mapk14 which are used in a combination with Sorafenib for use as a medicament for the treatment or prevention of liver cancer.
  • Inhibitors of the activity of Mapk14 are comprised in the group of small regulatory RNAs such as small inhibitory RNAs (siRNA), short hairpin RNA (shRNA) and microRNAs (miRNA), having a nucleic acid sequence hybridizing under physiological conditions, e.g. within a liver cell, to the mRNA encoding Mapk14 to reduce or inhibit the presence of Mapk14 in a hepatocyte or a liver cancer cell through RNA interference and accordingly inhibit the activity of Mapk14.
  • Small regulatory RNA molecules comprise or consist of the group containing at least one of the following inhibitory RNAs: SEQ ID NO: 1 to SEQ ID NO: 1364.
  • ShRNA molecules e.g. contained in microRNA molecules, hybridize to the mRNA encoding Mapk14.
  • the Mapk14 encoding gene gives rise to four mRNAs, which are regarded as splice products.
  • the splice product mRNAs are given as SEQ ID NO: 1365 to SEQ ID NO: 1368.
  • the shRNA of the invention through RNA interference reduce the expression, and hence the activity of Mapk14 gene product.
  • the inhibitory RNAs can be contained in classical antisense oligonucleotides for targeting the same mRNA regions for suppression of Mapk14 expression.
  • shRNA The specificity of shRNA, especially when the sequence encoding the shRNA was contained in a microRNA can also be shown in an vitro test using the reduction of the expression of a reporter gene product from a fusion gene, which produces a fusion mRNA that contains the coding sequence for both the reporter gene and for Mapk14.
  • the mRNA of the fusion gene which mRNA comprises the coding sequence for Mapk14 in combination with the coding sequence for the reporter gene, is reduced in the presence of an shRNA which is specific for the mRNA encoding Mapk14, whereas a control encoding an mRNA of the reporter gene only did not show a reduction of the reporter gene expression in the presence of an shRNA hybridizing to the mRNA encoding Mapk14.
  • the inactivation of Mapk14 by inhibiting or reducing the expression of Mapk14 in hepatocytes or liver cancer cells in experimental animals both by suppression of the expression of Mapk14 via continuous expression of an shRNA specific for the mRNA encoding Mapk14 in the mouse model, and by administration of a pharmaceutical composition, in which the pharmaceutical active agent consists of an shRNA specific for the mRNA encoding Mapk14 of the mouse reduces the present liver cancer or prevents the generation of liver cancer upon administration of agents which in the absence of the combination of a Mapk14 inhibitor and Sorafenib would induce a liver cancer.
  • the reduction or repression of Mapk14 activity by reducing or suppressing the expression of Mapk14 using the continuous expression of an shRNA which is specifically directed against the mRNA encoding Mapk14, or by administration of a pharmaceutical composition containing as the active ingredient or agent an shRNA specifically directed against the mRNA encoding Mapk14 in the animal model reduces a previously established liver cancer with increased efficacy upon administration of Sorafenib in comparison to the treatment with Sorafenib as the only pharmaceutical active agent, i.e. Sorafenib without the combination with an agent reducing Mapk14 activity.
  • the inhibitor of the activity of Mapk14 is at least one of the group comprising or consisting of inhibitors which have preference or specificity for inactivating the Mapk14 gene product, which compounds are given in the following table 1.
  • an inhibitor of Mapk14 according to the invention has an IC50 of at maximum 30 nM, preferably of at maximum 20 nM, more preferably of at maximum 10 nM or max. 5 nM or of at maximum 1 nM, most preferably of at maximum 0.1 or of at maximum 0.01 nM.
  • the IC50 is determined in an in vitro assay on Mapk14, e.g. determining the IC50 (inhibitory concentration for 50% inhibition) in dependence on the concentration of the inhibitor.
  • Mapk14 preferably having the human amino acid sequence and human structure, e.g. produced by expression of the human gene encoding Mapk14 in a human cell line, is isolated and incubated in a suitable buffer in the presence of a substrate to be phosphorylated, e.g. ATF-2, MAPKAPK-2 or Hsp27, 32 P- ⁇ -labelled ATP and the inhibitor.
  • a substrate to be phosphorylated e.g. ATF-2, MAPKAPK-2 or Hsp27
  • 32 P- ⁇ -labelled ATP is separated from the substrate, and the amount of 32 P-phosphorylation is determined, e.g. using scintillation counting.
  • the preferred substrate are ATF-2, MAPKAPK-2 or Hsp27 and a preferred buffer is: 20 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mg/ml BSA and protease inhibitor e.g. Complete mini (Roche), using incubation at room temperature or 37° C.
  • the inhibitor of Mapk14 has a lower IC50 than Sorafenib, which has an IC50 for Mapk14 of approx. 38 nM.
  • the inhibitory activity of the inhibitor of Mapk14 is determined in a cell-based in vitro assay using e.g. cancer cells, e.g. Hep3B.
  • the inhibitory activity of p38 inhibitors is determined for substrate protein of Mapk14 in relation to a housekeeping gene, e.g. ⁇ -tubulin.
  • cells are incubated with various concentrations of the inhibitor or carrier only respectively, e.g. for 2-4 days, and protein is extracted, e.g. using NP40-containing buffer.
  • phosphorylated substrate protein of Mapk14 is determined, e.g. by immunological detection of phosphorylated substrate protein, e.g. using a Western blot of SDS-PAGE separated cellular protein. For immunological detection, a phospho-specific antibody can be used.
  • a preferred substrate protein is ATF-2, MAPKAPK-2 and/or Hsp27.
  • the combination of Sorafenib with the additional inhibitor of Mapk14 of the invention in a cell-based assay has a significant higher toxicity or inhibition of proliferation rate against cultivated cancer cells, especially against liver cancer cells, e.g. against Hep3B.
  • cultivated living cells are counted following incubation with a combination of Sorafenib and the inhibitor of Mapk14 or with the same concentration of Sorafenib or inhibitor against Mapk14 alone or carriers, respectively, e.g. at concentrations of at maximum 20 ⁇ M, preferably at maximum 12 ⁇ m, more preferably at max. 5 ⁇ m. Significance can be determined using the two-tailed student's T-test.
  • the combination of Sorafenib and the inhibitor of Mapk14 according to the invention reduce cell proliferation of has an inhibitory effect on the cultivated cancer cells higher by at least a factor of 2, preferably at least by a factor of 4, more preferably at least by a factor of 10, in comparison to Sorafenib of the same concentration by itself.
  • X is O, S, SO, SO 2 , NR 7 , C ⁇ O, CHR 7 , —C ⁇ NOR 1 , —C ⁇ CHR 1 , or CHOR 1 ;
  • A is H, OH, an amine protecting group, Z n —NR 2 R 3 , Z n —NR 2 (C ⁇ O)R 2 , Z n —SO 2 R 2 , Z n —SOR 2 , Z n —SR 2 , Z n —OR 2 , Z n —(C ⁇ O)R 2 , Z n —(C ⁇ O)OR 2 , Z n —O—(C ⁇ O)R 2 , alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, hetero- alkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z
  • n 0 or 1
  • B is H, NH 2 , or substituted or unsubstituted methyl
  • A is H, OH, an amine protecting group, Z n —NR 2 R 3 , Z n —NR 2 (C ⁇ O)R 2 , Z n —SO 2 R 2 , Z n —SOR 2 , Z n —SR 2, Z n —OR 2 , Z n —(C ⁇ O)R 2 , Z n —(C ⁇ O)OR 2 , Z n —O—(C ⁇ O)R 2 , alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, hetero- alkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n —Ar 1 , wherein said alkyl, allyl, alkenyl
  • n is 0 or 1
  • 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid amide [5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-yl]morpholin-4-yl-methanone [5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-yl]-(4-methylpiperazin-1-yl)-methanone 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (1-benzyl-piperidin-4-yl)amide 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-benzylaminoethyl)amide 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-
  • substituents R1 to R14 can be selected independently from the group comprising CH 3 , CH 2 CH 3 , CH 2 CH 3 CH 3 , CH 2 (CH 2 ) 2 CH 3 , CH 2 ⁇ CH 2 , H, F, Cl, Br, I, SO 2 , CF 3 , N 3 , OH, NH 2 , ⁇ O, N(CH 3 ) 2 , OMe, OEt, SO 2 Me.
  • IC50 values are for Mapk14.
  • references to tradenames, trivial names and especially to publication number of patents or patent applications include the subject-matter of such references and publications into the present application, especially in respect of characterizations and methods for synthesis of the compounds.
  • FIG. 1 schematically shows the constructs used for genetically manipulating mice for generation of liver carcinomas with concurrent expression of shRNAs which can be non-specific or specific for the mRNA encoding Mapk14,
  • FIG. 2 shows the survival rates of mice expressing different shRNA molecules with and without administration of Sorafenib
  • FIG. 3 shows the detected levels of mRNA specific for Mapk14 with expression of shRNAs which are non-specific or specific for the mRNA encoding Mapk14
  • FIG. 4 shows a Western blot with specific detection for Mapk14 protein levels from cells expressing shRNA with or without specificity for Mapk14 mRNA, and with detection for ⁇ -tubulin as a loading control
  • FIG. 5 shows micrographs and GFP images of explanted mouse livers with and without administration of Sorafenib and expression of shRNAs specific for Mapk14 mRNA and controls
  • FIG. 6 schematically depicts the mechanism of the doxycycline dependent transcription of shRNAs and the GFP marker gene.
  • FIG. 7 shows the survival rates of mice treated with Sorafenib or a control compound (carrier) in the presence of the shRNA specific for the mRNA encoding Mapk14, (which transcription was activated 5 days after tumor development) and in the absence of the shRNA specific for the mRNA encoding Mapk14, as well as control shRNAs.
  • FIG. 8 shows the number of cells (as an indicator of proliferative activity) in an in vitro assay in which murine liver cancer cells were treated with Sorafenib in combination with the Mapk14 inhibitor BIRB-796,
  • FIG. 9 shows the number of cells (as an indicator of proliferative activity) in an in vitro assay, in which a human liver cancer cell line was treated with Sorafenib in combination with the inhibitor of Mapk14 BIRB-796,
  • FIG. 10 shows a picture of cell staining (cell density as an indicator of proliferative activity) (crystal violet assay) of a human liver cancer cell line after treatment of Sorafenib in combination with the Mapk14-specific inhibitor BIRB-796,
  • FIG. 11 shows the quantification of the number of dead cells (human liver cancer cell line) after treatment with Sorafenib in combination with the Mapk14-specific inhibitor BIRB-796 and controls, respectively,
  • FIG. 12 shows the number of cells in an in vitro assay in which a murine hepatocyte cancer cell line was treated with Sorafenib in combination with the Mapk14 inhibitor SB202190,
  • FIG. 13 shows the number of cells in an in vitro assay, in which a human liver cancer cell line was treated with Sorafenib in combination with the inhibitor of Mapk14 SB202190,
  • FIG. 14 shows a picture of cell staining (cell density as a marker for proliferative activity) of a human liver cancer cell line after treatment of Sorafenib in combination with the Mapk14-specific inhibitor SB202190,
  • FIG. 15 shows the quantification of the number of dead cells (human liver cancer cell line) after treatment with Sorafenib in combination with the Mapk14-specific inhibitor SB202190 and controls, respectively,
  • FIG. 16 shows the number of cells in an in vitro assay in which a murine liver cancer cell line was treated with Sorafenib in combination with the Mapk14 inhibitor SX011, and
  • FIG. 17 shows the number of cells in an in vitro assay, in which a human liver cancer cell line was treated with Sorafenib in combination with the inhibitor of Mapk14 SX011.
  • a genetically manipulated mouse model (p19 Arf ⁇ / ⁇ ) was generated, in which liver cancers were induced by a constitutive expression of the oncogenic NrasG12V mutant.
  • the nucleic acid construct for generating liver carcinomas is schematically shown in FIG. 1 , containing an expression cassette, wherein the coding sequence for NrasG12V is arranged between a 5′ promoter sequence and a 3′ polyadenylation site, which expression cassette is flanked by two inverted repeat elements (IR).
  • this nucleic acid construct was administered in combination with a nucleic acid construct containing an expression cassette for the transposase sleeping beauty 13 (SB 13) under the control of the constitutive phosphoglycerate kinase promoter (PGK).
  • SB 13 transposase sleeping beauty 13
  • PGK constitutive phosphoglycerate kinase promoter
  • the mouse model receiving both nucleic acid constructs shown in FIG. 1 was p19 Arf ⁇ / ⁇ , providing the genetic background sufficient for constitutive generation of murine liver cancer. Nucleic acid constructs were introduced into experimental mice using hydrodynamic tail vein injection.
  • mice that were genetically conditioned to develop liver cancer were treated with a pharmaceutical composition containing Sorafenib in a carrier, and carrier alone as a control.
  • the expression cassette in addition to the coding sequence for Nras12V contains the coding sequence for a short hairpin RNA as an example for an siRNA/shRNA.
  • an shRNA a non-specific shRNA (shcontrol) was used, an shRNA specific for the murine mRNA encoding murine Mapk14 (shMapk14.1095), and an alternative shRNA specific for the murine mRNA encoding Mapk14 (shMapk14.2590).
  • shRNA a non-specific shRNA (shcontrol) was used, an shRNA specific for the murine mRNA encoding murine Mapk14 (shMapk14.1095), and an alternative shRNA specific for the murine mRNA encoding Mapk14 (shMapk14.2590).
  • mice were mock-treated with carrier, or with Sorafenib alone.
  • FIG. 2 The survival curves are shown in FIG. 2 .
  • a liver cancer patient without a Mapk14 inhibitor is represented by the non-specific shRNA (1, shcontrol+carrier) and with the known treatment of Sorafenib (2, shcontrol+Sorafenib) according to the mouse model has an increased survival rate, whereas both mouse models in which the Mapk14 activity is inhibited by the shRNA specific for the mRNA encoding Mapk14 in combination with Sorafenib (4, shMapk14.1095+Sorafenib, and 6, shMapk14.2590+Sorafenib) have a significantly increased survival rate.
  • the inactivation of Mapk14 alone by an shRNA i.e.
  • FIG. 3 shows the levels of mRNA encoding Mapk14 in relation (%) to the non-specific control shRNA (shcontrol). It can be seen that the expression of each of shMapk14.1095 (SEQ ID NO: 1370) and shMapk14.2590 (SEQ ID NO: 1371) and of shMapk14.2364, which hybridize to the mRNA encoding Mapk14 results in a reduction of the mRNA encoding Mapk14 in the liver tissue.
  • FIG. 4 shows Western blot analyses of murine liver cancer cells with specific detection of Mapk14 and ⁇ -tubulin as a loading control. This analysis shows that the expression level of Mapk14 is significantly reduced by expression of shRNA specific for the mRNA encoding Mapk14, exemplified by shMapk14.1095, shMapk14.2590, and shMapk14.2364, whereas there is a drastically higher level of Mapk14 expression in the presence of shRNA (shcontrol) expression.
  • FIG. 5 shows photographs of livers explanted from the mouse model and the respective GFP—imaging of explanted mouse livers, confirming visually that in mouse models receiving no Sorafenib (top row, FIGS. 5.1, 5.2, 5.5, 5.6, 5.9, and 5.10 ) (carrier), the expression of a non-specific shRNA (shcontrol, FIGS. 5.1, 5.2 ) or of an shRNA inactivating Mapk14 (shMapk14.1095, shMapk14.2590, FIGS. 5.5, 5.6, 5.9, and 5.10 ) essentially do not reduce the development of liver cancer.
  • FIG. 5 The lower row of pictures of FIG. 5 ( FIGS. 5.3, 5.4, 5.7, 5.8, 5.11, and 5.12 ) shows that the inactivation of Mapk14, in this assay obtained in vivo by expression of an shRNA specific for the mRNA encoding Mapk14 (5.7, 5.8, 5.11, and 5.12) in the presence of treatment with Sorafenib drastically reduces the occurrence of liver cancer both in relation to the treatment with Sorafenib alone ( FIGS. 5.3 and 5.4 ) and in relation to expression of an inhibitory shRNA alone ( FIGS. 5.5, 5.6, 5.9, and 5.10 ).
  • the GFP imaging correlates with expression of NrasG12V positive tumors. Decreased GFP activity is observed for shRNAs shMapk14.1095 and shMapk14.2590 in the presence of Sorafenib, indicating reduction of cancer cells that were induced by the expression of Nras.
  • shRNA shMapk14.1095
  • the shRNA was provided by controlled expression using an expression cassette which is under the control of a tetracycline response element (TRE) of the otherwise constitutive viral promoter (P minCMV ).
  • the expression cassette contains the coding sequence for a shRNA molecule and the coding sequence of a GFP marker gene.
  • the nucleic acid construct containing the expression cassette for the shRNA molecule and the coding sequence of a GFP marker gene under the control of the Tet-inducible promoter also contains a constitutive expression cassette for rtTA (rtetRVP16), which in the presence of Doxycycline (DOX) binds to the TRE and activates the promoter of the expression cassette encoding a fusion of shRNA and GFP.
  • rtTA rtetRVP16
  • FIG. 6 schematically shows the nucleic acid constructs and the mechanism for inducing transcription of shRNA and GFP encoding sequence.
  • the nucleic acid construct of FIG. 6 is introduced into experimental mice via retroviral infection of cancer cells which after selection are injected into the liver of wildtype mice.
  • the injected mice then develop liver carcinomas in which Mapk14 can be conditionally inactivated by inducing transcription of the shRNA by addition of DOX.
  • FIG. 7 shows the result of an experiment using the expression of an shRNA specific for the mRNA encoding murine Mapk14, namely shMapk14.1095, or a non-specific shRNA (shcontrol).
  • the administration of DOX induces inactivation of Mapk14 by inducing transcription of the shRNA and GFP.
  • murine liver cancer cells (Nras arf ⁇ / ⁇ ) were cultivated. Cultivated cells were treated with 10 ⁇ M Sorafenib, 2 ⁇ M BIRB, 12 ⁇ M BIRB and with a combination of 10 ⁇ M Sorafenib+2 ⁇ M BIRB, or a combination of 10 ⁇ M Sorafenib+12 ⁇ M BIRB.
  • a parallel assay was made, replacing Sorafenib or Mapk14 inhibitors by formulation agents without pharmaceutical active agent (carrier).
  • FIG. 8 shows the results of the viable cell count after two days of treatment of the murine cancer cells and FIG. 9 shows the viable cell count after 7 days of treatment of the cultivated human liver cancer cell line (Hep3B) with the combinations of 2 ⁇ M Sorafenib, 2 ⁇ M BIRB, 12 ⁇ M BIRB, a combination of 2 ⁇ M Sorafenib+2 ⁇ M BIRB, or a combination of 2 ⁇ M Sorafenib+12 ⁇ M BIRB, respectively, in the left columns, whereas samples without pharmaceutical active agent (carrier) are shown as right hand columns.
  • Hep3B cultivated human liver cancer cell line
  • FIG. 10 shows crystal violet staining of cultivated human liver cancer cells which are cultivated and treated for 7 days with 2 ⁇ M Sorafenib, 12 ⁇ M BIRB-796, or a combination of 2 ⁇ M Sorafenib+12 ⁇ M BIRB-796 (upper row), controls without kinase inhibitor are shown in the lower row (carrier).
  • This view of the culture plates makes it evident that the combination of Sorafenib with an inhibitor for Mapk14, represented by BIRB-796, increases the efficacy of Sorafenib.
  • the dead cell count of FIG. 11 using trypane blue staining of the cultivated human liver cancer cells (Hep3B) shows that the increase in dead cells in the presence of an inhibitor (left hand columns) was more prominent for the combination of Sorafenib with BIRB-796 over Sorafenib or BIRB-796 alone, and over the control (carrier, right hand columns) without a kinase inhibitor.
  • SB 202190 was tested in an in vitro assay of the murine liver cancer cells (Nras Arf ⁇ / ⁇ ) and the human liver cancer cell line (Hep3B).
  • FIG. 12 shows the results of the viable cell count after two days of treatment of the murine cancer cells and FIG. 13 shows the viable cell count after 7 days of treatment of the cultivated human liver cancer cell line (Hep3B) with the combinations of 2 ⁇ M Sorafenib, 2 ⁇ M SB202190, 12 ⁇ M SB202190, a combination of 2 ⁇ M Sorafenib+2 ⁇ M SB202190, or a combination of 2 ⁇ M Sorafenib+12 ⁇ M SB202190, respectively, in the left columns, whereas samples without pharmaceutical active agent (carrier) are shown as right hand columns.
  • Hep3B cultivated human liver cancer cell line
  • FIG. 14 shows the crystal violet staining of cultivated human liver cancer cells which are cultivated and treated for 7 days with 2 ⁇ M Sorafenib, 12 ⁇ M SB202190, or a combination of 2 ⁇ M Sorafenib+12 ⁇ M SB202190 (upper row), controls without kinase inhibitor are shown in the lower row (carrier).
  • This view of the culture plates makes it evident that the combination of Sorafenib with an inhibitor for Mapk14, represented by SB202190, increases the efficacy of Sorafenib.
  • the dead cell count shown in FIG. 15 (left hand columns indicate counts in presence of inhibitor, right hand columns are control with carrier only) supports the finding that the combination of the Mapk14 inhibitor SB202190 with Sorafenib is significantly more effective than Sorafenib or SB202190 alone.
  • FIG. 16 shows the results of the viable cell counts after two days of treatment of the murine cancer cells
  • FIG. 17 shows the viable cell count after 7 days of treatment of the cultivated human liver cancer cell line (Hep3B) with the combinations of 10 ⁇ M or 2 ⁇ M Sorafenib, 52 ⁇ M or 22 ⁇ M SX 011, and a combination of 10 or 2 ⁇ M Sorafenib+52 or 22 ⁇ M SX 011 respectively, in the left hand columns, whereas samples without pharmaceutical active agent (carrier) are shown as right hand columns.
  • Hep3B cultivated human liver cancer cell line

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US14/131,059 2011-07-08 2012-07-09 Medicament for treatment of liver cancer Expired - Fee Related US10441577B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/131,059 US10441577B2 (en) 2011-07-08 2012-07-09 Medicament for treatment of liver cancer

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
EP11173379 2011-07-08
EP11173379.6 2011-07-08
EP11173379A EP2543372A1 (de) 2011-07-08 2011-07-08 Medikament zur Behandlung von Leberkrebs
US201161508368P 2011-07-15 2011-07-15
EP12161141.2 2012-03-23
EP12161141 2012-03-23
EP12161141 2012-03-23
EP12162905 2012-04-02
EP12162905.9 2012-04-02
EP12162905 2012-04-02
US14/131,059 US10441577B2 (en) 2011-07-08 2012-07-09 Medicament for treatment of liver cancer
PCT/EP2012/063445 WO2013007708A1 (en) 2011-07-08 2012-07-09 Medicament for treatment of liver cancer

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/063445 A-371-Of-International WO2013007708A1 (en) 2011-07-08 2012-07-09 Medicament for treatment of liver cancer

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/569,109 Division US20200000787A1 (en) 2011-07-08 2019-09-12 Medicament for treatment of liver cancer

Publications (2)

Publication Number Publication Date
US20150079154A1 US20150079154A1 (en) 2015-03-19
US10441577B2 true US10441577B2 (en) 2019-10-15

Family

ID=47505540

Family Applications (2)

Application Number Title Priority Date Filing Date
US14/131,059 Expired - Fee Related US10441577B2 (en) 2011-07-08 2012-07-09 Medicament for treatment of liver cancer
US16/569,109 Abandoned US20200000787A1 (en) 2011-07-08 2019-09-12 Medicament for treatment of liver cancer

Family Applications After (1)

Application Number Title Priority Date Filing Date
US16/569,109 Abandoned US20200000787A1 (en) 2011-07-08 2019-09-12 Medicament for treatment of liver cancer

Country Status (5)

Country Link
US (2) US10441577B2 (de)
EP (2) EP3111937B1 (de)
ES (1) ES2627120T3 (de)
HK (1) HK1232158A1 (de)
WO (1) WO2013007708A1 (de)

Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102827073A (zh) 2011-06-17 2012-12-19 安吉奥斯医药品有限公司 治疗活性组合物和它们的使用方法
US9474779B2 (en) 2012-01-19 2016-10-25 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
SG11201505515XA (en) 2012-01-27 2015-09-29 Univ Leland Stanford Junior Methods for profiling and quantitating cell-free rna
GB201306901D0 (en) * 2013-04-16 2013-05-29 Chroma Therapeutics Ltd Combination
US9579324B2 (en) 2013-07-11 2017-02-28 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
EP3019480B1 (de) 2013-07-11 2020-05-06 Agios Pharmaceuticals, Inc. 2,4- oder 4,6-diaminopyrimidin-verbindungen als idh2-mutanten-inhibitoren für die behandlung von krebs
WO2015003355A2 (en) * 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
WO2015003360A2 (en) 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US20150031627A1 (en) 2013-07-25 2015-01-29 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
CN103751221B (zh) * 2014-01-23 2016-08-17 中国人民解放军第三军医大学第一附属医院 Sirt1抑制剂联合索拉菲尼在制备治疗肝癌的药物中的应用
CA2941084A1 (en) * 2014-02-28 2015-09-03 Mirna Therapeutics, Inc. Sorafenib-microrna combination therapy for liver cancer
KR102400737B1 (ko) 2014-03-14 2022-05-20 아지오스 파마슈티컬스 아이엔씨. 치료적으로 활성인 화합물의 약제학적 조성물
MX2017009608A (es) 2015-01-30 2017-11-20 Univ Sydney Compuestos anticancerigenos.
PE20171789A1 (es) * 2015-03-02 2017-12-28 Bristol Myers Squibb Co Inhibidores del factor beta de crecimiento de transformacion (tgf-beta)
MD3362066T2 (ro) 2015-10-15 2022-08-31 Les Laboratoires Servier Sas Terapie combinată pentru tratamentul tumorilor maligne
EP4403173A3 (de) 2015-10-15 2024-10-09 Les Laboratoires Servier Kombinationstherapie zur behandlung von malignitäten
WO2018021827A1 (en) * 2016-07-29 2018-02-01 Chong Kun Dang Pharmaceutical Corp. Compositions for treating liver cancer comprising a vascular disrupting agent
ES2927104T3 (es) 2016-09-09 2022-11-02 Incyte Corp Derivados de pirazolopiridina como moduladores de HPK1 y usos de los mismos para el tratamiento del cáncer
WO2018049191A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridone derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049214A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
AR109595A1 (es) 2016-09-09 2018-12-26 Incyte Corp Compuestos de pirazolopirimidina y usos de estos como inhibidores de hpk1
WO2018152220A1 (en) 2017-02-15 2018-08-23 Incyte Corporation Pyrazolopyridine compounds and uses thereof
WO2018153373A1 (zh) * 2017-02-27 2018-08-30 贝达药业股份有限公司 Fgfr抑制剂及其应用
US11197872B2 (en) 2017-04-21 2021-12-14 Lunella Biotech, Inc. Vitamin C and doxycycline: a synthetic lethal combination therapy for eradicating cancer stem cells (CSCs)
CA3060509A1 (en) * 2017-04-21 2018-10-25 Federica Sotgia Targeting hypoxic cancer stem cells (cscs) with doxycycline: implications for improving anti-angiogenic therapy
GB201706806D0 (en) * 2017-04-28 2017-06-14 Sentinel Oncology Ltd Pharmaceutical compounds
CR20190524A (es) 2017-05-19 2020-01-10 Lunella Biotech Inc Antimitoscinas: inhibidores específicos de la biogénesis mitocondrial para erradicar células madre cancerosas
US12006553B2 (en) 2017-05-19 2024-06-11 Lunella Biotech, Inc. Companion diagnostics for mitochondrial inhibitors
US11091485B2 (en) 2017-05-23 2021-08-17 Shengke Pharmaceuticals (Jiangsu) Ltd. Imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine compound as protein kinase inhibitor
CR20200033A (es) 2017-06-26 2020-03-05 Lunella Biotech Inc Mitocetoscinas: agentes terapéuticos basados en mitocondrias que fijan como objetivo el metabolismo de cetonas en células cancerosas
WO2019051199A1 (en) 2017-09-08 2019-03-14 Incyte Corporation 6-CYANO-INDAZOLE COMPOUNDS AS HEMATOPOIETIC PROGENITOR KINASE 1 (HPK1) MODULATORS
WO2019071147A1 (en) 2017-10-05 2019-04-11 Fulcrum Therapeutics, Inc. INHIBITORS OF KINASE P38 REDUCING EXPRESSION OF DUX4 GENE AND DOWNSTREAM GENES FOR THE TREATMENT OF FSHD
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
CN111655249A (zh) * 2017-11-14 2020-09-11 蒙彼利埃地区癌症研究所 用于治疗前列腺癌的活性物的组合
EP3720436A4 (de) 2017-12-06 2021-06-02 Lin Bioscience, Pty Ltd. Tubulinhemmer
SI3755703T1 (sl) 2018-02-20 2022-11-30 Incyte Corporation N-(fenil)-2-(fenil)pirimidin-4-karboksamidni derivati in sorodne spojine kot zaviralci HPK1 za zravljenje raka
US10752635B2 (en) 2018-02-20 2020-08-25 Incyte Corporation Indazole compounds and uses thereof
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
MA53726A (fr) 2018-09-25 2022-05-11 Incyte Corp Composés pyrazolo[4,3-d]pyrimidine en tant que modulateurs des alk2 et/ou fgfr
GB2612911B (en) 2019-02-14 2023-11-22 Mirvie Inc Methods and systems for determining a pregnancy-related state of a subject
TW202114680A (zh) 2019-08-06 2021-04-16 美商英塞特公司 Ｈｐｋ１抑制劑之固體形式
GB201915828D0 (en) * 2019-10-31 2019-12-18 Cancer Research Tech Ltd Compounds, compositions and therapeutic uses thereof
US11316208B2 (en) 2020-07-08 2022-04-26 American Hyperform, Inc. Process for recycling cobalt and nickel from lithium ion batteries
US11909016B2 (en) 2021-08-24 2024-02-20 American Hyperform, Inc. Recycling process for isolating and recovering rare earth metals and nickel hydroxide from nickel metal hydride batteries
IT202200000314A1 (it) * 2022-01-11 2023-07-11 Universita’ Degli Studi Di Parma Composto e composizione per il ripristino metabolico e funzionale dei linfociti nk nell’epatocarcinoma e relativo metodo
US11993580B1 (en) 2022-12-02 2024-05-28 Neumora Therapeutics, Inc. Methods of treating neurological disorders

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000042012A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
WO2005009961A2 (en) 2003-07-23 2005-02-03 Bayer Pharmaceuticals Corporation Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
CN101317832A (zh) 2007-06-06 2008-12-10 周亚伟 白藜芦醇口服纳米给药系统
WO2010128259A1 (fr) 2009-05-07 2010-11-11 Sanofi-Aventis Combinaison antitumorale comprenant l'ave8062 et le sorafenib
US20120115862A1 (en) * 2008-10-09 2012-05-10 Stefan Laufer Dibenzocycloheptatone derivatives and pharmaceutical agents containing said compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101237036B1 (ko) * 2009-11-04 2013-02-25 성균관대학교산학협력단 안티센스 가닥에 의한 오프-타겟 효과를 최소화한 신규한 ｓｉＲＮＡ 구조 및 그 용도

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000042012A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
WO2005009961A2 (en) 2003-07-23 2005-02-03 Bayer Pharmaceuticals Corporation Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
CN101317832A (zh) 2007-06-06 2008-12-10 周亚伟 白藜芦醇口服纳米给药系统
US20120115862A1 (en) * 2008-10-09 2012-05-10 Stefan Laufer Dibenzocycloheptatone derivatives and pharmaceutical agents containing said compounds
WO2010128259A1 (fr) 2009-05-07 2010-11-11 Sanofi-Aventis Combinaison antitumorale comprenant l'ave8062 et le sorafenib
US20120108641A1 (en) 2009-05-07 2012-05-03 Sanofi Antitumor combination including ave8062 and sorafenib

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
Abou-Alfa et al. (JCO Sep. 10, 2006 vol. 24 No. 26 4293-4300). *
Balkwill (Cancer and Metastasis Reviews Sep. 2006, vol. 25, Issue 3, pp. 409-416). *
Hui et al, 2007, Cell Cycle 6:20, pp. 2429-2433.
Huynh, Hung, "Molecularly targeted therapy in hepatocellular carcinoma", Biochemical Pharmacology, 80 (2010) pp. 550-560.
Liu Cancer Res 2006; 66: (24). Dec. 15, 2006, (Year: 2006). *
Llovel, J. et al., "6519 Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma (HCC): collective results from the phase III sorafenib HCC assessment randomized protocol (SHARP) and Asia-Pacific trials", Joint ECCO 15-34th ESMO Multidisciplinary Congress, Sep. 2009, vol. 7, No. 2, p. 367.
Llovel, J. et al., "6519 Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma (HCC): collective results from the phase III sorafenib HCC assessment randomized protocol (SHARP) and Asia-Pacific trials", Joint ECCO 15—34th ESMO Multidisciplinary Congress, Sep. 2009, vol. 7, No. 2, p. 367.
Min, Lihua, et al., "Mitogen-activated protein kinases in hepatocelluclar carcinoma development", Seminars in Cancer Biology, 21, (2011) pp. 10-20.
Noel, J. Kay, et al., "Systematic review to establish the safety profiles for direct and indirect inhibitors of p38 Mitogen-activated protein kinases for treatment of cancer", Med Oncol, (2008) 25, pp. 323-330.
Parekh, Palak, et al., "Downregulation of cyclin D1 is associated with decreased levels of p38 MAP kinases, Akt/PKB and Pak1 during chemopreventive effects of resveratrol in liver cancer cells", Experimental and Toxicological Pathology, 63 (2011) pp. 167-173.
Stepniak et al, 2006, Genes & Development, 20:2306-2314.
Unknown: "Nexavar: EPAR-all authorized publications", Internet Mar. 4, 2007, Retrieved from the Internet: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR-All Authorised_presentations/human/000690/WC500027706.pdf [retrieved on Nov. 24, 2011] (1 page).
Unknown: "Nexavar: EPAR—all authorized publications", Internet Mar. 4, 2007, Retrieved from the Internet: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR—All Authorised_presentations/human/000690/WC500027706.pdf [retrieved on Nov. 24, 2011] (1 page).
Wagner et al. (Nature Reviews Cancer vol. 9 Aug. 2009 p. 537-549). *

Also Published As

Publication number Publication date
US20150079154A1 (en) 2015-03-19
EP3111937A1 (de) 2017-01-04
EP3111937B1 (de) 2020-06-17
ES2627120T3 (es) 2017-07-26
EP2729146A1 (de) 2014-05-14
HK1232158A1 (zh) 2018-01-05
US20200000787A1 (en) 2020-01-02
EP2729146B1 (de) 2017-03-08
WO2013007708A1 (en) 2013-01-17

Similar Documents

Publication Publication Date Title
US10441577B2 (en) Medicament for treatment of liver cancer
US20190099453A1 (en) Medicament for liver regeneration and for treatment of liver failure
Parrish et al. Efflux transporters at the blood-brain barrier limit delivery and efficacy of cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor model
US20040106605A1 (en) Synergistic methods and compositions for treating cancer
Prete et al. Pericytes elicit resistance to vemurafenib and sorafenib therapy in thyroid carcinoma via the TSP-1/TGFβ1 axis
Song et al. A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment
RU2695228C2 (ru) Прерывистое введение ингибитора mdm2
US10314834B2 (en) Therapeutic agent or treatment method for Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia (ALL) having IKZF1 mutation
US20080219977A1 (en) Combinations Comprising Gemcitabine and Tyrosine Kinase Inhibitors for the Treatment of Pancreatic Cancer
US10463649B2 (en) Inhibitors of Mc1-1 as drugs to overcome resistance to BRAF inhibitors and MEK inhibitors
EP2543372A1 (de) Medikament zur Behandlung von Leberkrebs
US20160303137A1 (en) Dual pi3k and wnt pathway inhibition as a treatment for cancer
US20160151406A1 (en) Combination cancer therapy with c-met inhibitors and synthetic oligonucleotides
US20210030718A1 (en) Combinations for treating cancer
EP3479843A1 (de) Verwendung von nox-inhibitoren zur behandlung von krebs
Markowitz et al. Pharmacological inhibition of the protein kinase MRK/ZAK radiosensitizes medulloblastoma
US20050171182A1 (en) Methods and compositions for use in the treatment of mutant receptor tyrosine kinase driven cellular proliferative diseases
WO2019110139A1 (en) New compounds for use as a therapeutically active substance and in particular for use in the treatment of tumors
Failly et al. Combination of sublethal concentrations of epidermal growth factor receptor inhibitor and microtubule stabilizer induces apoptosis of glioblastoma cells
US20210308106A1 (en) Methods and pharmaceutical compositions for the treatment of systemic mastocytosis
KR20240112932A (ko) 암 치료를 위한 cdk2 억제제 및 cdk4 억제제를 포함하는 방법 및 투여 섭생법
US10144723B2 (en) Treatment of solid tumors by inhibiting MRK/ZAK
US20220354874A1 (en) Therapeutic compositions and methods for treating cancers
US20050075358A1 (en) Methods for treating IGF1R-inhibitor induced hyperglycemia
US11684672B2 (en) Combinations of copanlisib with anti-PD-1 antibody

Legal Events

Date Code Title Description
AS Assignment

Owner name: HELMHOLTZ ZENTRUM FUER INFEKTIONSFORSCHUNG, GERMAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ZENDER, LARS;RUDALSKA, RAMONA;DAUCH, DANIEL;REEL/FRAME:032650/0018

Effective date: 20140121

STCV Information on status: appeal procedure

Free format text: APPEAL BRIEF (OR SUPPLEMENTAL BRIEF) ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS

STPP Information on status: patent application and granting procedure in general

Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20231015